Contamination Filter for Mass Spectrometer

ABSTRACT

Methods and systems for performing mass spectrometry are provided herein. In accordance with various aspects of the applicants&#39; teachings, the methods and systems can utilize an ion mobility spectrometer operating at atmospheric or low-vacuum pressure to remove the major contributors to the contamination and degradation of critical downstream components of a mass spectrometer located within a high-vacuum system (e.g., ion optics, mass filters, detectors), with limited signal loss.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/894,494, filed Nov. 27, 2015, filed as Application No.PCT/IB2014/001143 on Jun. 20, 2014, which claims priority to U.S.Provisional Patent Application No. 61/838,185, filed on Jun. 21, 2013,and U.S. Provisional Patent Application No. 62/014,657, filed on Jun.19, 2014, the disclosures of which are incorporated by reference hereinin their entireties.

FIELD

The invention generally relates to mass spectrometry, and moreparticularly to methods and apparatus utilizing an ion mobilityspectrometer to remove contamination and prevent degradation ofdownstream components of a mass spectrometer operating in a high-vacuumchamber.

INTRODUCTION

Mass spectrometry (MS) is an analytical technique for determining theelemental composition of test substances with both qualitative andquantitative applications. For example, MS can be useful for identifyingunknown compounds, determining the isotopic composition of elements in amolecule, determining the structure of a particular compound byobserving its fragmentation, and quantifying the amount of a particularcompound in a sample. Mass spectrometers have been widely used in thefields of chemistry and physics for over a century, and increasingly inbiology over the past several decades. Sub-disciplines such asenvironmental monitoring for pollutants, forensic analysis for drugs ofabuse and toxins, biomedical research, clinical disease diagnostics,food analysis, material science, and others, have been utilizingatmospheric pressure ionization mass spectrometers toward greatpractical value and to help achieve significant advancements in thesefields. Large numbers of highly complex samples have been interrogatedfor the identity and quantity of a variety of chemical constituents atlevels as low as parts per trillion.

As a result, mass spectrometry instrumentation has evolved towardincreased selectivity as mass spectrometric detection and quantificationof analytes contained within complex matrices generally requires highresolution separation techniques to reduce the effect of interferingspecies within the sample. Despite advances in MS that have enabledhigh-resolution mass analyzers to distinguish target species frominterfering species within about 0.01 Th, it is not always feasible orpossible to use a high-resolution mass analyzer to separate interferingspecies, for example, due to availability, cost, and/or experimentalconditions.

Accordingly, various approaches for increasing the resolution ofanalytes have been developed including, for example, improved samplepreparation techniques prior to ionization such as liquidchromatography, derivatization prior to LC separation, solid-phaseextraction, or turbulent-flow chromatography. Additionally, varioustechniques have been developed to separate charged species within anionized sample based on characteristics beyond mass-to-charge ratio(m/z). By way of example, whereas MS generally analyzes ions based ondifferences in m/z, ion mobility spectrometry (IMS) and other ionmobility separation techniques (e.g., differential mobility spectrometry(DMS), high field asymmetric waveform ion mobility spectrometry (FAIMS),Field Ion Spectrometry (FIS)) instead separate ions based upon otherfactors such as size, shape, and charge state as ions drift through agas (typically at atmospheric pressure) in an electric field. The drifttime through an electrostatic field is characteristic of the mobility ofthe ion (e.g., its size and shape and its interactions with thebackground gas), or in the case of DMS and FAIMS devices, thecompensation voltage (CV or CoV) required to preferentially prevent thedrift of a particular species is characteristic of its differentialmobility. However, operating parameters for ion mobility spectrometers,however, are conventionally configured to optimize the resolution of thevarious charged species generated from the sample (e.g., to separateisobaric species), often at the expense of decreased transmission ofions of interest. Moreover, the effects of ion mobility conditions onparticular species can be unpredictable and often lead to ion loss(i.e., decreased signal/sensitivity).

Additionally, the ion optics and other mass analyzer components, whichare located deep inside high-vacuum chambers where ion trajectories canbe precisely controlled by electric fields, are delicate and prone tofouling by the excessive sample loads and debris generated byatmospheric pressure ion sources. While, ionization at atmosphericpressure, whether by chemical ionization processes or by electrospray,is generally a highly efficient means of generating ions and microampsof ion current of the analyte(s) of interest, contaminating/interferingions can also be created in high abundance at ion current levels far inexcess of the analyte(s) of interest. The undesirable transport ofcontaminating ions and charged particles from the atmospheric pressuresource region to the high-vacuum chamber of a mass spectrometer can alsoresult in contamination of ion optics within the intermediate pumpingstages of a differentially pumped mass spectrometer. Such contaminationcan not only interfere with the mass spectrometric analysis, but alsolead to increased costs or decreased throughput necessitated by thecleaning of critical components within the high-vacuum chamber andintermediate pressure regions. Because of the higher sample loads andcontaminating nature of the biologically based samples being analyzedwith current day atmospheric pressure ionization sources, reduction ofsystem contamination remains a critical concern.

The concept of using a differential ion mobility (DMS) device as apre-filter to a mass spectrometer (MS) has been developed by severalgroups. This includes the use of high field asymmetric waveform ionmobility spectrometers (FAIMS) which operate on the same principles ofutilizing the difference in ions high and low field mobility to effectseparations. The expressed purpose for coupling DMS with MS has been toincrease the selectivity of the mass spectrometer by providing a highresolution ion mobility device that can separate ion species that a massspectrometer cannot, thus increasing the specificity of the system byhyphenating two instruments that separate ions on different principles,i.e. the mobility and mass measurements are orthogonal to each other(Schneider et al, Int. J. Ion Mobility Spec., 2013, 16, 207-216). Theseparation of isobaric species is an example of something a DMS devicecan do in many cases but a mass spectrometer cannot. Compounds withdifferent primary, secondary, or tertiary structures having the samemass (isobaric) have been shown to separate with differential ionmobility thereby improving the selectivity of the mass spectrometer whenused in combination with such a device. Also, isobaric compounds withdifferent gas phase ion chemistries can be separated by DMS addingfurther resolving power to the mass spectrometer. As such, the focus onthe design of such mobility systems has been toward the improvement ofthe resolution and peak capacity. Resolution (Rs) is defined in equation1 as:

$\begin{matrix}{{Rs} = \frac{{Co}\; V}{F\; W\; H\; M}} & \left( {{Equation}\mspace{14mu} 1} \right)\end{matrix}$

where CoV represents the compensation voltage required to pass aspecific ion through the cell and FWHMis the full width half maximum inVolts of the peak generated during a scan of the CoV. Resolution, asdefined here, provides an indication of the CoV shift and differentialmobility peak width for a single compound.

Peak capacity (Pc) is defined as:

Pc=CoV range/FWHM   (Equation 2)

where CoV range is the compensation range in Volts over which a largenumber of compounds is spread and FWHMis the average full width halfmaximum in Volts of the peaks generated during a scan of the CoV for alarge number of compounds. The peak capacity is an indicator of thenumber of compounds that can be separated in a complex mixture.

A third important performance characteristic of a DMS cell is theefficiency with which it transmits ions though the mobility analyzerdefined as:

Te=Sd/S   (Equation 3)

where Te is the ion transmission efficiency, Sd is the number of ionsmeasured by the mass spectrometer detector with the DMS filter installedand filtering and S is the number of ions measured by the massspectrometer detector with no DMS filter installed on the massspectrometer. Transmission efficiency indicates how many ions are lostin the DMS cell.

Transmission efficiency tends to run counter to both resolution and peakcapacity. That is in order to maximize resolution and peak capacity, thetransmission efficiency is compromised. As mentioned above, the currentthinking in the field of differential ion mobility instrumentation is tomaximize selectivity, i.e. resolution and peak capacity. An example ofthis is illustrated in the designs of Shvartsburg (Shvartsburg, A. A.;Smith, R. D. 2013. “Separation of protein conformers by differential ionmobility in hydrogen rich gases” Anal. Chem. 85, 6967-6973) which setthe current record for DMS devices achieving resolution values of about400-500.

For purposes of illustration, refer to FIG. 3 which defines theimportant parameters of the cell dimensions. FIG. 3 shows a schematic ofa rectangular, planar DMS sensor. The separation occurs in the gapbounded by the electrodes where the RF field is applied. Cell dimensionsand power supply specifications can take on a wide variety of dimensionsand values depending on the applications and specifications targeted.One typical set of specifications for a high resolution device are 1 mmgap height, 30 mm length, and 10 mm width powered with a 3 MHz RFasymmetric waveform generator having a typical maximum output of 3000 V0-peak.

FIG. 4A shows a schematic of a stand-alone DMS sensor. The ion filterregion is comprised of two planar, parallel electrodes. Faraday platesat the exit serve as the detector for positive and negative ionssimultaneously. FIG. 4B shows a schematic of a DMS with a massspectrometer as the ion detector and depiction of the asymmetricwaveform, where the integrated time/voltage areas under the low and highfield portions within each period are the same. The RF waveform is drawnas an idealized square wave but not all DMS power supplies are designedto deliver square wave functions for practical reasons related to powerconsumption. The amplitude of the waveform is referred to as theseparation voltage (SV). The compensation voltage (CoV) is a DCpotential applied to an electrode used to counteract the ion's migrationtoward an electrode in response to the SV, its magnitude is proportionalto the ion's differential mobility. It is shown as a voltage ramp here,but can be set to a fixed value to allow targeted ions to pass throughthe DMS, while excluding non-targeted ions. For illustration purposes,the DMS of FIG. 4B is shown in front of the mass spectrometer inlet withno additional sealing means. In practice, ion transmission from the DMScell to the mass spectrometer is usually maximized by providing sealingmeans.

FIG. 5 shows more details of a DMS-MS system. The design of the DMS cellinvolves balancing the various dimensions of length, width, gap height,gas velocity, RF frequency, amplitude, and waveform shape to achieve thedesired performance specifications tailored to a specific application.The time an ion spends inside the cell is of particular importance withregards to the ultimate resolution, peak capacity, and transmissionefficiency. This is referred to as the flight time or equivalently theresidence time. The flight time (τ) can be calculated from Equation 4:

$\begin{matrix}{\tau = \frac{l\; w\; h}{Q}} & \left( {{Equation}\mspace{14mu} 4} \right)\end{matrix}$

where l, w, h, and Q are the sensor length, width, height, andvolumetric gas flow, respectively.

FIG. 5 shows a DMS coupled to a mass spectrometer where the maximumtransport gas flow rate is determined by the vacuum drag of the MS andcan be reduced in a controlled manner by a variable leak, referred to asthe throttle gas, used to adjust resolution. The throttle gas can alsobe reversed to draw thereby increasing the velocity of the transport gasbeyond that provided by the vacuum system. This feature would reduceresolution and improve ion transmission. This approach for DMS couplingis the subject of Applicants' U.S. Pat. Nos. 8,084,736 and 8,513,600herein incorporated by reference. The curtain gas supplies both thetransport gas and counter current flow which keeps uncharged atmosphericcontaminants out of the transport gas.

All aspects of the design of a DMS cell are parametric, i.e. they arehighly interdependent. There is no particular dimension, ratio ofdimensions, or RF frequency, amplitude, or waveform that can be expectedto provide optimal performance for the primary figures of meritsimultaneously, those figures of merit being resolution, peak capacity,and ion transmission efficiency (sensitivity). The design of the celland its power supplies will accentuate some of these figures of meritwhile at the same time compromising others. A clear understanding of thedesired application is required to define the performance specificationfor each of these figures of merit, which then will establish thegeneral direction of the design of the cell. To date, the evolution ofDMS instrumentation has been toward improvements in resolution and peakcapacity.

Three examples of altering various aspects of the design of a particularcell and the effect that has on the performance characteristics ofresolution, peak capacity, and transmission will follow to serve asexamples. The cell used in these examples had dimensions of 1×10×30 mmfor gap height, width, and length, respectively, with the alterations asdescribed. The general trends that the performance characteristicsdisplay as the design is altered in the fashion described in theseexamples would be similar regardless of what other specific geometriesor power supply specifications were to be used.

FIGS. 6A and 6B are examples of the improvement in the resolution of aDMS device by optimizing the design to increase the flight timedescribed by Schneider B B, Nazarov E G, Covey T R., “Peak Capacity inDifferential Mobility Spectrometry: Effects of Transport Gas and GasModifiers”, Int. J. Ion Mobil. Spectrom., 2012a, 15, 141-150. FIGS. 6Aand 6B show ionograms of a six component mixture of drugs showing theeffect of residence time on resolution in a DMS coupled to a massspectrometer. The term ionogram was coined to describe this form of dataacquisition where the CoV is scanned at a constant SV, while a sample isintroduced over the time frame of the scan (Guevremont R., “High-FieldAsymmetric Waveform Ion Mobility Spectrometry: A New Tool for MassSpectrometry”, J. Chrom. A., 2004, 1058, 3-19). The intensities of thesignals from the components of the sample are recorded during the scanand the resolution and peak capacity of the separation can bedetermined. FIG. 6A has a 6.5 ms residence time. FIG. 6B has a 20 msresidence time. Residence time can be controlled by several meansincluding altering the transport gas flow rate and/or the dimensions ofthe cell. The sample was composed of 1) phenylalanine, 2) histidine, 3)methylhistamine, 4) minoxidil, 5) cimetidine, and 6) perphenazine,infused into an electrospray ion source at 10 μL/min. The signal wasmonitored for each component by multiple reaction monitoring (MRM) on atriple quadrupole MS. Increasing the flight time provides a narrowing ofthe observed mobility peaks, but does not change the CoV. Improvedresolution is observed with increasing flight time; however the peakintensity decreases as a result of increased ion losses due to diffusionprocesses in the mobility analyzer.

FIGS. 7A-7D show examples of the changes in the peak capacity of a DMSdevice resulting from altering the gap height over a range of a) 0.25mm, b) 0.50 mm, c) 1 mm, and d) 1.5 mm. As described in Equation 2, peakcapacity, for a particular separation, is defined as the ratio of theCoV range over which the specified compound set is spread divided by theFWHM of individual peaks. The measured CoV for a given compound scaleswith the gap height. However, the limiting peak width for the 4 DMSsensors used to generate these data was similar. Therefore, the peakcapacity improved with increased gap height, predominantly because therange of CoV voltages over which this compound set was spread increasedsubstantially more than the average FWHM. The peak capacities rangedfrom 10.5 to 38.5 for the smallest to the largest gap height sensors,respectively.

The improvement in transmission efficiency for methylhistamine ions(1×10×30 mm cell dimensions) as the separation voltage increased is seenin FIG. 8. Ionograms are shown at three different separation voltagesdemonstrating increasing ion signal with increasing SV. The upper limitsto the SV are determined by other aspects of the cell geometry, inparticular gap height. A practical limit is reached when the fieldbetween the cells (V/mm) reaches the discharge limit causing a breakdownof the transport gas and electrical arcing between the electrodes.

The above three examples illustrate some of the effects on theperformance characteristics of resolution, peak capacity, and iontransmission efficiency that the key design elements of separationvoltage, gap height, and ion flight time affect. Although the data wereobtained with specific geometries and power supplies, the trends can begeneralized to any particular DMS or FAIMS design. As mentioned earlier,the current status in the development of DMS-MS devices by bothcommercial and non-commercial researchers has been in the direction ofimprovements to resolution and peak capacity as the first consideration.Transmission efficiency is also considered, but it plays a secondaryrole to the optimization of selectivity.

Accordingly, there remains a need for methods and systems that enablethe analysis of increasingly complex samples with improved sensitivity,while reducing potential sources for contamination.

SUMMARY

The present teachings are based on the unexpected discovery that the useof ionization sources operating at atmospheric pressure (e.g.,electrospray and chemical ionization sources) can lead to the formationof high mass ions (e.g., charged solvent clusters) that can pass throughinterface regions that include counter-current gas flows (curtain gas)and contaminate the optics of an ion spectrometer as well as severelydegrade the signal-to-noise ratio, for example, by generating largesignal transients. In some cases, these high mass ions can have a massgreater than about 2000 amu, e.g., in a range of about 2000 amu up toand greater than 2,000,000 amu. It has additionally been discovered thatan ion mobility spectrometer can be configured to filter out these highmass ions while ensuring that a substantial portion of the chargedspecies of interest (e.g., at least about 50%, or at least about 70%, orat least about 90%) pass through the ion mobility spectrometer foranalysis by a downstream mass analyzer.

The present teachings are based on the unexpected discovery that a hightransmission, low resolution ion mobility spectrometer device can filterthe high mass ions or charged debris to keep the vacuum system of a massspectrometer clean for long periods of time. The device configurationtakes into account the residence time of the ions through the ionmobility spectrometer, the gap height between the electrodes of the ionmobility spectrometer, and the maximum separation voltage applied to theelectrodes of the ion mobility spectrometer, wherein a ratio of theresidence time of the ions through the ion mobility spectrometer to theproduct of gap height between the electrodes of the ion mobilityspectrometer and the maximum separation voltage applied to theelectrodes of the ion mobility spectrometer being less than 0.002. Invarious aspects, a ratio of the residence time of the ions through theion mobility spectrometer to the product of gap height between theelectrodes of the ion mobility spectrometer and the maximum separationvoltage applied to the electrodes of the ion mobility spectrometer beingless than 0.0015.

Accordingly, in various aspects, certain embodiments of the Applicants'teachings relate to a method of operating a mass spectrometer system,the method comprising providing an ion source for ionizing a sample togenerate a plurality of ions, providing a low resolution, hightransmission ion mobility spectrometer for reducing contamination,introducing said plurality of ions into an input end of the ion mobilityspectrometer, transporting said plurality of ions in a drift gas throughthe ion mobility spectrometer from the input end to an output endthereof, providing a mass spectrometer in fluid communication with thedifferential mobility spectrometer for receiving the ions from theoutput end of differential mobility spectrometer, and a ratio of theresidence time of the ions through the ion mobility spectrometer to theproduct of gap height between electrodes of the ion mobilityspectrometer and the maximum separation voltage applied to theelectrodes of the ion mobility spectrometer being less than 0.002. Invarious aspects, a ratio of the residence time of the ions through theion mobility spectrometer to the product of gap height between theelectrodes of the ion mobility spectrometer and the maximum separationvoltage applied to the electrodes of the ion mobility spectrometer beingless than 0.0015.

In various aspects, the residence time of the ions can be less than 100ms. In various aspects, the gap height can be between 0.02 and 5millimeters. In various aspects, the SV comprises an RF signal appliedto the electrodes, and including a CoV comprised of a DC signal appliedto the electrodes, and wherein the RF and DC signals are configured togenerate a fringing field in proximity of said input end of the ionmobility spectrometer effective to cause said ions having a selectedmass to follow off-axis trajectories to collide with said electrodes inproximity to said input end. In various aspects, the method furthercomprises selecting a transit time of the ions through the ion mobilityspectrometer to facilitate transit of analytes of interest through theion mobility spectrometer. In various aspects, the transit time can beselected to provide transmission efficiency of greater than 50% for abroad mass range of ions. In various aspects, the ion mobilityspectrometer comprises a differential mobility spectrometer or a FAIMSsystem.

In various aspects, certain embodiments of the Applicants' teachingsrelate to a system for analyzing ions comprising an ion source, a lowresolution, high transmission ion mobility spectrometer for reducingcontamination having an input end for receiving ions from source and anoutput end, the ion mobility spectrometer having an internal operatingpressure, electrodes, and at least one voltage source for providing DCand RF voltages to the electrodes, a mass spectrometer in fluidcommunication with the differential mobility spectrometer for receivingthe ions from the output end of differential mobility spectrometer, acontroller operably coupled to the ion mobility spectrometer andconfigured to control the DC and RF voltages; and a ratio of theresidence time of the ions through the ion mobility spectrometer to theproduct of gap height between electrodes of the ion mobilityspectrometer and the maximum separation voltage applied to theelectrodes of the ion mobility spectrometer being less than 0.002. Invarious aspects, a ratio of the residence time of the ions through theion mobility spectrometer to the product of gap height between theelectrodes of the ion mobility spectrometer and the maximum separationvoltage applied to the electrodes of the ion mobility spectrometer beingless than 0.0015.

In various aspects, the residence time of the ions can be less than 100milliseconds. In various aspects, the gap height can be between 0.02 and5 millimeters. In various aspects, the separation voltage (SV) comprisesan RF signal applied to the electrodes, and including a compensationvoltage (CoV) comprised of a DC signal applied to the electrodes, andwherein the RF and DC signals are configured to generate a fringingfield in proximity of said input end of the ion mobility spectrometereffective to cause said ions having a selected mass to follow off-axistrajectories to collide with said electrodes in proximity to said inputend. In various aspects, the system further comprises selecting atransit time of the ions through the ion mobility spectrometer tofacilitate transit of analytes of interest through the ion mobilityspectrometer. In various aspects, the transit time can be selected toprovide transmission efficiency of greater than 50% for a broad massrange of ions. In various aspects, the ion mobility spectrometercomprises a differential mobility spectrometer or a FAIMS system.

In some embodiments, the ion mobility spectrometer can also beconfigured to filter out not only the above-described high mass ions,but also ions having an m/z less than a threshold (e.g., 100, 150, or200 amu), also referred to herein as low-mass ions. Such low mass ionscan be created in high abundance due to the large number of moleculessubjected to ionization at atmospheric pressures (e.g., in the presenceof ambient molecules within the atmospheric or near-atmosphericchamber). For example, in some cases, when liquid samples are introducedinto an atmospheric pressure ion source, the solvent molecules canproduce ion current levels far in excess of the ion current associatedwith the analyte(s) of interest in the sample. The removal of suchunwanted low-mass ions can, for example, improve the signal-to-noiseprovided by a downstream mass analyzer.

Accordingly, the methods and systems described herein can be effectiveto reduce the amount of unwanted charged material from entering thevacuum system, thereby maintaining peak performance of the massspectrometer systems over longer periods of time and during heavy use.While the operating parameters of ion mobility spectrometers areconventionally configured to maximize resolution (e.g., to separateisobaric species while maintaining sufficient signal to resolve peaks),the present teachings are based in part on the discovery that an ionmobility spectrometer can be configured to operate in a low resolutionmode, e.g., operating at a high transmission efficiency with broad peaksto maximize the transit of the species of interest through thespectrometer and thereby improve sensitivity, while nonethelessfiltering out high mass and low mass species. In some embodiments, themethods and systems according to the present teachings can be employedto remove up to about 99% of unwanted ions generated by the ion source,while allowing the ions of interest to pass to a downstream massanalyzer.

In accordance with various aspects, certain embodiments of theapplicants' teachings relate to a method of operating a massspectrometer system including an ion mobility spectrometer (e.g., adifferential mobility spectrometer or FAIMS) and a mass spectrometer influid communication with the ion mobility spectrometer. According to themethod, a sample is ionized to generate a plurality of ions, which areintroduced into an input end of the ion mobility spectrometer. As theplurality of ions are transported in a drift gas through the ionmobility spectrometer from the input end to an output end thereof, ionshaving a mass less than about 200 amu (e.g., less than about 150 amu orless than about 100 amu) and greater than about 2000 amu (e.g., in arange of about 2000 amu to about 2,000,000 amu) are filtered from thedrift gas as the plurality of ions are transported within the ionmobility spectrometer. The method can also include introducing ionsexiting the output end of the ion mobility spectrometer into the massspectrometer.

In some aspects, the filtering steps can comprise diverting (e.g.,deflecting) a portion of the ions to collide with at least one electrodeof said ion mobility spectrometer. In various aspects, filtering ions orcharged particles having a mass greater than about 2000 amu comprisesapplying an RF signal to electrodes of the ion mobility spectrometer,the RF signal having an amplitude and frequency configured to cause saidions having a mass greater than about 2000 amu to follow unstabletrajectories.

In accordance with some aspects, the ion mobility spectrometer comprisesat least a pair of electrodes having a separation voltage and acompensation voltage applied thereto, the method further comprisingselecting a CoV such that a broad mass range of analytes are transportedthrough the ion mobility spectrometer to exit through said output endthereof. For example, in some aspects, the combination of CoV and SV cancomprise RF and DC signals applied to at least one of the electrodesconfigured to generate a fringing field in proximity of said input endof the ion mobility spectrometer effective to cause said ions having amass greater than 2000 amu to follow off-axis trajectories to collidewith said electrodes in proximity to said input end.

In various aspects, the transit time of the ions through the ionmobility spectrometer can be selected to facilitate transit of analytesof interest through the ion mobility spectrometer. For example, thetransit time can be selected to provide transmission efficiency ofgreater than 50% or more for a broad mass range of ions. By way ofexample, the transit time can be less than about 7 ms, less than about 6ms, less than about 5 ms, and less than about 2 ms, in variousembodiments that include a 1 mm gap height between electrodes. Invarious embodiments, the transmit time may vary depending upon gapheight or separation voltage. In some aspects, the transit time can beselected to minimize losses of ions within a selected mass or m/z range.For example, the transit time can be selected such that ions enteringthe input end of the ion mobility spectrometer and having a mass in therange of about 200 amu to about 2000 amu are preferentially transportedto the output end of the ion mobility spectrometer. In related aspects,the ions having a mass in the range of about 200 amu to about 2000 amucan be substantially unresolved at the output end of the ion mobilityspectrometer. In this manner, the differential ion mobility spectrometeroperates in a broad band pass mode, rather than the ion resolving modeused in the prior art. In some aspects, the ion mobility spectrometercan be configured with gas flows and cell dimensions scaled to provideresolutions sufficiently low to provide transmission efficienciesgreater than 50% for a broad mass range of interest.

In some embodiments, the gas flow rate through the ion mobilityspectrometer can be selected to ensure that ions of interest transitthrough the spectrometer with minimal loss, if any, e.g., a loss of lessthan about 50%, less than about 20%, or less than about 10%, while thehigh mass and low mass ions are filtered out. In various aspects, themethod can comprise selecting a flow rate of the drift gas through theion mobility spectrometer such that the transit time is less than about1 ms and providing transmission efficiencies greater than about 50% fora broad mass range. By way of example, the flow rate of the drift gasthrough the ion mobility spectrometer can be greater than about 5 L/minfor providing efficiencies greater than about 50% for a broad mass rangewhen using electrode dimensions of 1×10×30 mm.

In accordance with another aspect, certain embodiments of theapplicants' teachings relate to a method of operating a massspectrometer system including an ion mobility spectrometer and a massspectrometer in fluid communication with the ion mobility spectrometer.According to the method, a sample can be ionized to generate a pluralityof charged species and the charged species can be introduced into aninput end of the ion mobility spectrometer. Ions of said charged specieshaving a mass in a range from about 200 amu to about 2000 amu can bepreferentially transported to an output end of the ion mobilityspectrometer, the gas flows and cell dimensions of the operating ionmobility spectrometer (e.g., non-zero DC and/or RF voltages beingapplied thereto) being configured to provide transmission efficienciesgreater than 50% for a broad mass range.

In accordance with some aspects, certain embodiments of the applicants'teachings relate to a system for analyzing ions comprising an ion source(e.g., an atmospheric pressure ion source) and an ion mobilityspectrometer having an input end for receiving ions from the ion sourceand an output end, the ion mobility spectrometer having an internaloperating pressure, electrodes, and at least one voltage source forproviding DC and RF voltages to the electrodes. The system furtherincludes a mass spectrometer in fluid communication with thedifferential mobility spectrometer for receiving the ions from theoutput end of the differential mobility spectrometer. A controller canbe operably coupled to the ion mobility spectrometer and configured tocontrol the DC and RF voltages such that the ion mobility spectrometerpreferentially transports ions having a mass in a range from about 200amu to about 2000 amu to the output end of the ion mobilityspectrometer. In some aspects, the controller can be configured tooperate the ion mobility spectrometer with a transmission efficiency ofgreater than 50% for a broad mass range.

In some aspects, the controller can be configured to modulate the RF andDC potentials applied to the electrodes so as to generate a fringingfield in proximity to the input end of the ion mobility spectrometer,the fringing field configured to filter ions having a mass greater thanabout 2000 amu (e.g., in a range of about 2000 amu to about 2,000,000amu) or less than about 200 amu, from the ions received from the ionsource. Alternatively or additionally, the controller can be configuredto modulate the DC and RF potentials applied to the electrodes such thations having a mass less than about 200 amu are filtered as the ionsreceived from said source are transported through the ion mobilityspectrometer.

In various aspects, a vacuum chamber can surround the mass spectrometerfor maintaining the mass spectrometer at a vacuum pressure lower thanthe internal operating pressure of the ion mobility spectrometer, thevacuum chamber being operable to draw a drift gas flow including theions through the differential mobility spectrometer and into the vacuum.Multiple differentially pumped vacuum stages, including ion transportoptics may be disposed between the atmospheric pressure inlet and thehigh-vacuum region containing the mass analyzer. The system canadditionally include a gas port for modifying a gas flow rate throughthe ion mobility spectrometer, the gas port being located between theion mobility spectrometer and the mass spectrometer. In related aspects,the controller can be configured to modulate the gas flow rate throughthe ion mobility spectrometer and the at least one voltage source suchthat the ion mobility spectrometer can be modulated between alow-resolution mode in which the transmission efficiency is greater than50% for a broad mass range of ions and a high-resolution mode in whichions can be resolved based on their mobility in the ion mobilityspectrometer. In some aspects, the gas flow rate in the low-resolutionmode is greater than the gas flow rate in the high-resolution mode. Forexample, the gas flow rate in the low-resolution mode can be greaterthan about 5 L/min. By way of example, the gas flow rate in thelow-resolution mode can be scaled with the cell dimensions to provide atransmission efficiency greater than 50%.

In accordance with some aspects, certain embodiments of the applicants'teachings relate to a mass spectrometer system including a mass analyzerlocated in a high vacuum chamber for analyzing sample ions formed atatmospheric pressure and directed to the analyzer through anintermediate atmospheric pressure chamber. The intermediate atmosphericpressure chamber can include at least one pair of electrodes inopposition to each other defining a path through which the ions travel,said path including a region of defocusing electric fringe fields; meansassociated with the opposing electrodes for deflecting charged clustersand/or debris having an m/z greater than a first threshold within a gasstream entering an input end of the plurality of electrodes, thedeflection preventing the charged clusters and/or debris from enteringthe high vacuum chamber; means associated with the opposing electrodesfor deflecting unwanted ions having an m/z lower than a second thresholdsuch that said ions of lower m/z are prevented from entering the highvacuum chamber; and means for providing a high volumetric gas flowthrough the plurality of electrodes, the gas flow being configured fortransporting the ions to the mass spectrometer with minimal loss of ionsin a m/z range between the lower m/z and the higher m/z.

These and other features of the applicants' teachings are set forthherein.

BRIEF DESCRIPTION OF THE DRAWINGS

The skilled person in the art will understand that the drawings,described below, are for illustration purposes only. The drawings arenot intended to limit the scope of the applicants' teachings in any way.

FIG. 1(A) depicts MS/MS data of a sample containing reserpine (609.2m/z), with Q1 filtering ions less than about 1000 m/z and with thecollision energy in Q2=47 eV.

FIG. 1(B) depicts data from an “Asteroid scan” of a sample containingreserpine (609.2 m/z), with Q1 filtering ions less than about 1000 m/zand with the collision energy in Q2=50 eV.

FIG. 1(C) depicts data from an “Asteroid scan” of a sample containingreserpine (609.2 m/z), with Q1 filtering ions less than about 1000 m/zand with the collision energy in Q2=100 eV.

FIG. 2, in a schematic diagram, illustrates an exemplary massspectrometry system including a differential mobility spectrometer inaccordance with various aspects of the applicants' teachings.

FIG. 3 shows a schematic of a rectangular, planar DMS sensor inaccordance with various aspects of the applicant's teachings.

FIG. 4A shows a schematic of a stand-alone DMS sensor in accordance withvarious aspects of the applicants' teachings.

FIG. 4B shows a schematic of a DMS with a mass spectrometer as the iondetector and depiction of the asymmetric waveform in accordance with theapplicant's teachings.

FIG. 5 shows an example of a commercial DMS coupled to a massspectrometer in accordance with the applicants' teachings.

FIGS. 6A and 6B show ionograms illustrating the effect of residence timeon resolution in a DMS coupled to a mass spectrometer in accordance withthe applicants' teachings.

FIGS. 7A-7D show ionograms illustrating the changes in the peak capacityof a DMS device resulting from altering gap height in accordance withthe applicants' teachings.

FIG. 8 shows ionograms of methylhistamine at different separationvoltages demonstrating an increase in ion transmission with increasingseparation voltage in accordance with the applicants' teachings.

FIGS. 9A-9C show contamination from charged debris in accordance withthe applicants' teachings.

FIGS. 10A-10B show the inlet orifice from a mass spectrometer and lenselements inside the vacuum in accordance with the applicants' teachings.

FIG. 11 shows the filtering of debris material by the DMS fields inaccordance with the applicants' teachings.

FIG. 12 shows the effect of gap height between the DMS electrodes ontransmission, resolution, and peak capacity, in accordance with theapplicants' teachings.

FIG. 13 shows the effect of separation voltage applied to the DMSelectrodes on transmission, resolution, and peak capacity, in accordancewith the applicants' teachings.

FIG. 14 shows the effect of residence time of ions in the DMS ontransmission, resolution, and peak capacity, in accordance with theapplicants' teachings.

FIG. 15 shows the effect of RT Index on transmission, resolution, andpeak capacity in accordance with the applicants' teachings.

FIGS. 16A-16B show elimination of contamination by the filter inaccordance with the applicants' teachings.

FIG. 17 shows a comparison of the contamination filter and a highresolution DMS in accordance with the applicants' teachings.

FIGS. 18A-18D show contamination being kept out of the vacuum system andthe ion entrance aperture of the mass spectrometer in accordance withthe applicants' teachings.

FIG. 19 shows simulations of ions and charged particle trajectories inthe entrance region of the DMS cell in accordance with the applicants'teachings.

DETAILED DESCRIPTION

It will be appreciated that for clarity, the following discussion willexplicate various aspects of embodiments of the applicants' teachings,while omitting certain specific details wherever convenient orappropriate to do so. For example, discussion of like or analogousfeatures in alternative embodiments may be somewhat abbreviated.Well-known ideas or concepts may also for brevity not be discussed inany great detail. The skilled person will recognize that someembodiments of the applicants' teachings may not require certain of thespecifically described details in every implementation, which are setforth herein only to provide a thorough understanding of theembodiments. Similarly it will be apparent that the describedembodiments may be susceptible to alteration or variation according tocommon general knowledge without departing from the scope of thedisclosure. The following detailed description of embodiments is not tobe regarded as limiting the scope of the applicants' teachings in anymanner.

Methods and systems for performing mass spectrometry utilizing an ionmobility spectrometer are provided herein. In accordance with variousaspects of the applicants' teachings, the methods and systems describedherein can be effective to reduce the amount of unwanted chargedmaterial from entering the vacuum system by deflecting this chargedmaterial to non-critical surfaces located in the atmospheric region ofthe instrument, where they can be readily accessed, cleaned and/orreplaced. In some aspects, intervals between maintenance of vacuumsystem components may be increased by at least an order of magnitude.

While the operating parameters of ion mobility spectrometers areconventionally configured to optimize resolution (e.g., by separatingisobaric species), the present teachings provide an ion mobilityspectrometer operating in a low resolution mode to optimize the transitof the species of interest through the spectrometer and thereby improvesensitivity, while filtering out unwanted high mass and low massspecies.

As indicated above, the present teachings are based in part on thediscovery that the use of ionization sources operating at atmosphericpressure (e.g., electrospray and chemical ionization sources) can leadto the formation of high mass ions (e.g., charged solvent clusters) thatmay pass through mass spectrometer inlets that include curtain gasprotection. With reference now to FIG. 1(A), a product ion chromatogramis shown in which a sample containing 10 μg/uL of reserpine wassubjected to atmospheric pressure ionization and run through MS/MSanalysis (without utilizing a front-end ion mobility spectrometer inaccordance with the present teachings) utilizing a QTRAP® 5500 systemmarketed by AB Sciex. The collision energy was 47 eV. Fragmentation ofreserpine ions is observed, with a wealth of daughter ions, includingm/z 174 and 195.

FIGS. 1(B) and 1(C) demonstrate results of an experiment where Q1 wasconfigured to open resolution at m/z 1250 such that ions at an m/z lessthan about 1000 were filtered. The remaining ions and charged particleswere transported to Q3 and subjected to collision energies ramped from 0eV to 150 eV as the spectra of the product ions were detected. Asexpected, at 0 eV, no ion signal was observed as the reserpine ions arebelow the filter threshold (XIC not shown). However, as the collisionenergy increases, the product ion scan indicates the presence of severalpeaks characteristic of both reserpine precursor ions (609.2 m/z) aswell as common product ions (e.g., 195.1 m/z) of reserpine. Withoutbeing bound by any particular theory, the presence of these peaks isbelieved to demonstrate that although Q1 was set to filter reserpineprecursor ions and other ions having m/z less than about 1000, precursorreserpine ions nonetheless entered Q2 as part of a massive chargedresidue. Such charged residues formed during electrospray ionization ofhigh concentration samples incorporate a large amount of mass beyond themass range of mass spectrometers (i.e., the reason why no signal wasobserved at 0 eV), and as will be appreciated by a person skilled in theart in light of the present teachings. The presence of such high masscharged residues might not only degrade the signal-to-noise ratio, forexample, by generating unwanted, unexpected, or interfering productions, but could also contaminate critical components within the vacuumchamber housing the mass analyzer components or ion optics. FIGS. 1(B)and 1(C) show results using collision energies of 50 eV and 100 eV,respectively. Because most biological samples (e.g., blood plasma)include high concentrations of background matrix material that couldco-elute with an analyte of interest from an LC column and generate highmass charged residues that would follow the same field lines as the ionsof interest, the residues from these samples could be observed as largesignal transients as they hit the electron multiplier detector, therebycreating noise spikes that severely degrade signal to noisemeasurements. This is particularly problematic with analogue detectioncircuits because each individual residue carries thousands of charges.Since this material has the ability to penetrate deep into the ionoptics of the mass spectrometer by virtue of its charge, it is a majorsource of serious ion optic contamination and performance loss.

In some cases, these high mass ions can have a mass greater than about2000 amu, e.g., in a range of about 2000 amu up to and greater than2,000,000 amu. As discussed below, the present teachings provide an ionmobility spectrometer configured to filter out these high mass ionswhile ensuring that a substantial portion of the charged species ofinterest (e.g., at least about 50%, or at least about 70%, or at leastabout 90%) pass through the ion mobility spectrometer for analysis by adownstream mass analyzer.

Additionally, in accord with various aspects of the present teachings,the ion mobility spectrometer can be configured to filter out not onlythe above-described high mass ions, but also ions having an m/z lessthan a threshold (e.g., 100, 150, or 200 amu). Such low mass ions can becreated in high abundance due to the large number of molecules subjectedto ionization at atmospheric pressure (e.g., in the presence of ambientmolecules within the atmospheric or near-atmospheric chamber). Forexample, in some cases, when liquid samples are introduced into anatmospheric pressure ion source, the solvent molecules can produce ioncurrent levels far in excess of the ion current associated with theanalyte(s) of interest in the sample. The removal of such unwantedlow-mass ions can, for example, improve the signal-to-noise provided bya downstream mass analyzer.

While the operating parameters of ion mobility spectrometers areconventionally configured to optimize the resolution provided by thespectrometer (e.g., to separate isobaric species), the present teachingsprovide an ion mobility spectrometer configured to operate in a lowresolution mode, e.g., operating at a resolution sufficiently low toprovide transmission efficiencies of greater than 50% for a broad massrange through the spectrometer and thereby improve sensitivity, whilefiltering out high mass and low mass species. In various embodiments,the methods and systems according to the present teachings can beemployed to remove up to about 99% of unwanted ions generated by the ionsource, while allowing the ions of interest to pass to a downstream massanalyzer.

With reference now to FIG. 2, an exemplary ion mobilityspectrometer/mass spectrometer system 100 in accordance with variousaspects of Applicants' teachings is illustrated schematically. As shownin FIG. 2, the ion mobility spectrometer/mass spectrometer system 100generally comprises a differential mobility spectrometer 110 in fluidcommunication with a first vacuum lens element 150 of a massspectrometer (hereinafter generally designated mass spectrometer 150).As will be appreciated by a person skilled in the art, the ion mobilityspectrometer/mass spectrometer system 100 represents only one possibleconfiguration for use in accordance with various aspects of the systems,devices, and methods described herein. The mobility spectrometer 110 canhave a variety of configurations, but is generally configured to resolveions based on their mobility through a fixed or variable electric field.For example, the mobility spectrometer can be any of an ion mobilityspectrometer, a differential mobility spectrometer, or FAIMS devices ofvarious geometries such as parallel plate, curved electrode, orcylindrical FAIMS device, among others.

In the exemplary embodiment depicted in FIG. 2, the differentialmobility spectrometer 110 comprises a pair of opposed electrode plates112 surrounded by an electrical insulator 114 that supports theelectrode plates 112 and insulates them from other conductive elements.The electrode plates 112 surround a drift gas 116 that drifts from aninput end or inlet 118 of the differential mobility spectrometer 110 toan outlet or output end 120 of the differential mobility spectrometer110. Differential mobility spectrometry applies RF voltages, referred toherein as separation voltages (SV), across the electrode plates 112 togenerate an electric force in a direction perpendicular to that of thedrift gas flow. Ions of a given species tend to migrate radially awayfrom the axis of the drift tube by a characteristic amount during eachcycle of the RF waveform due to differences in mobility during the highfield and low field portions. A DC CoV, is applied to the electrodeplates 112 to provide a counterbalancing electrostatic force to that ofthe SV.

In accordance with various aspects of the present teachings, acontroller 122 can be operably coupled to the differential mobilityspectrometer 110 and configured to control the DC and RF voltagesapplied to the electrodes such that ions having a mass in a selectedrange from about 200 amu to about 2000 amu (or in a range from about 100amu to about 2000 amu, or in a range of about 150 amu to about 2000 amu)are preferentially transmitted to the outlet end 120. By way of example,the controller can be configured to modulate the RF and DC potentialsapplied to the electrodes so as to generate a fringing field inproximity to the input end 118 of the differential mobility spectrometer110. Applicants have discovered that such a fringing field can beeffective, for example, to deflect ions having a mass greater than about2000 amu (e.g., in a range of about 2000 amu to about 2,000,000 amu) orless than about 200 amu from the axis of the differential mobilityspectrometer such that these ions are neutralized (i.e., collide) withthe electrodes proximate to the inlet 118. Additionally oralternatively, the controller can control the CoV and SV applied to theelectrode plates 112, for example, such that low-mass ions (e.g., ionshaving a mass less than about 200 amu) are deflected into the electrodes112 as they are transported through the differential mobilityspectrometer 110 while entrained in the drift gas 116. Without beingbound by an particular theory, it is believed that low mass ions exhibitincreased mobility and/or experience an increased force as they aretransmitted through the electric field within the differential mobilityspectrometer such that the deflection of these low-mass ions issufficient such that these ions collide with the electrodes 112. In someaspects, the controller can be configured to operate the differentialmobility spectrometer at a resolution of less than about 10, 5, or 1.

The outlet end 120 of the differential mobility spectrometer 110releases the drift gas 116 and ions transmitted through the differentialmobility spectrometer 110 towards an inlet 154 of a vacuum chamber 152containing the mass spectrometer 150.

The drift time through the flight tube and therefore the mobility of anion is characteristic of the size and shape of the ion and itsinteractions with the background gas. As shown in FIG. 2, thedifferential mobility spectrometer 110 can be contained within a curtainchamber 130 that is defined by a curtain plate or boundary member 132and is supplied with a curtain gas from a curtain gas supply 134.Specifically, curtain gas from curtain gas supply 134 can flow throughcurtain gas conduit 136 at flow rates determined by a flow controllerand valves. The curtain gas supply 134 can provide any pure or mixedcomposition curtain gas to the curtain gas chamber. By way ofnon-limiting example, the curtain gas can be air, O₂, He, N₂, CO2, orany combination thereof. The pressure of the curtain gases in thecurtain chamber 130 can be maintained at or near atmospheric pressure(i.e., 760 Torr). Additionally, the curtain gas can be modified with anytype of modifier or mixture of modifiers known in the art for purposessuch as clustering, suppressing discharge, limiting proton transfer,chemically modifying ions, forming complexes or bonds or other purposes.

Ions can be provided from an ion source (not shown) and emitted into thecurtain chamber 130 via curtain chamber inlet 144. As will beappreciated by a person skilled in the art, the ion source can bevirtually any ion source known in the art, including for example, acontinuous ion source, a pulsed ion source, an atmospheric pressurechemical ionization (APCI) source, an electrospray ionization (ESI)source, an inductively coupled plasma (ICP) ion source, amatrix-assisted laser desorption/ionization (MALDI) ion source, a glowdischarge ion source, an electron impact ion source, a chemicalionization source, or a photoionization ion source, among others. Thepressure of the curtain gases in the curtain chamber 130 (e.g., ˜760Torr) can provide both a curtain gas outflow 142 out of curtain gaschamber inlet 144, as well as a curtain gas inflow 137 into thedifferential mobility spectrometer 110, which inflow 137 becomes thedrift gas 116 that carries the ions through the differential mobilityspectrometer 110 and into the mass spectrometer 150 contained within thevacuum chamber 152, which can be maintained at a much lower pressurethan the curtain chamber 130. For example, the vacuum chamber 152 can bemaintained at a pressure of 2.3 Torr by a vacuum pump.

As shown in FIG. 2, the ion mobility system/mass spectrometer system 100can additionally include a port 124 and a vacuum pump 126 locatedbetween the outlet end 120 of the differential mobility spectrometer 110and an inlet 154 of a vacuum chamber 152, through which gas can be drawnout of the curtain chamber 130. It will be appreciated by a personskilled in the art, that by increasing the rate at which gas is drawnthrough the port 124, the gas flow rate of the drift gas 116 through thedifferential mobility spectrometer 110 can be increased, therebydecreasing the transit time of ions travelling therethrough.

Thus, whereas prior art differential mobility spectrometers areconfigured to optimize selectivity (e.g., by increasing transit time ofthe drift gas 116 such that the target analyte can be separated from aninterfering species at the expense of sensitivity (i.e., throughneutralization of the interfering species on the electrodes by tuningthe CV to preferentially transmit an ion of interest or by altering theCV such that peaks between various species can be resolved as the CV isramped), systems in accord with the present teachings exhibit transittimes that minimize losses (e.g., maximize transmission, increasing peakwidth and height) of species exhibiting a broad range of m/z andmobilities.

By way of example, in systems in accord with the present teachings, thedrift gas 116 can impart transit times for the ions through thedifferential mobility spectrometer 110 of less than 7 ms (e.g., 6.5 ms,less than 5 ms, less than 2 ms, less than 1 ms). Though such transittimes can result in the differential mobility spectrometer exhibiting areduced resolution, the drift gas 116 flow rate through the ion mobilityspectrometer 110 can ensure that ions of interest transit through thespectrometer with minimal loss, if any, e.g., a loss of less than about50%, or less than about 20%, or less than about 10%, while the high mass(e.g., greater than 2000 amu) and low mass ions (e.g., less than 200amu) are filtered out (e.g., deflected off-axis so as to collide with anelectrode 112) as discussed otherwise herein.

Moreover, it will be appreciated in light of the present teachings thatother variables can be selected so as to maximize transmission throughthe ion mobility spectrometer. By way of non-limiting example, thedimensions of the differential mobility spectrometer 110, the number gasdensity, the pressure of the curtain chamber, and/or the flow rate ofthe drift gas can be modulated so as to optimize transmission. Forexample, the ion mobility spectrometer can be configured with gas flowsand cell dimensions scaled to provide resolutions sufficiently low toprovide transmission efficiencies greater than 50% for a broad massrange of interest. By way of non-limiting example, in an ion mobilityspectrometer having a length of about 30 mm (1×10×30 mm) along itstransmission axis and a distance between electrodes of about 1 mm, aflow rate of about 3.8 L/min can result in a residence time of about 4.2ms while a flow rate of about 6.5 L/min can result in a residence timeof about 1.8 msec.

With reference again to FIG. 2, the mass spectrometer system 100 can beoperated so as to set the flow rate of the drift gas 116 with the port124 closed to about 2.8 L/min, by way of non-limiting example. Invarious embodiments, the port 124 can be opened and the pump 126operated such that the flow rate increases to a rate, e.g., greater thanabout 4 L/min, greater than about 5 L/min, greater than about 6 L/min,or about 7 L/min. It will further be appreciated that the differentialmobility spectrometer 110 can also be dimensioned so as to provide adecreased path length (e.g., shorter electrode plates 112) to reducetransit time. Thus, the present teachings enable that the transit timeof ions through the differential mobility spectrometer 110 can beselected to optimize transmission of ions of interest through thedifferential mobility spectrometer 110 into the mass analyzer 150.

As will be appreciated by a person skilled in the art, the massspectrometer 150 can additionally include mass analyzer elements 150 adownstream from vacuum chamber 152. Ions can be transported throughvacuum chamber 152 and may be transported through one or more additionaldifferentially pumped vacuum stages containing one or more mass analyzeror ion transport elements 150 a. For instance, in one embodiment, atriple quadrupole mass spectrometer may comprise three differentiallypumped vacuum stages, including a first stage maintained at a pressureof approximately 2.3 Ton, a second stage maintained at a pressure ofapproximately 6 mTorr, and a third stage maintained at a pressure ofapproximately 10⁻⁵ Torr. The third vacuum stage can contain a detector,as well as two quadrupole mass analyzers with a collision cell locatedbetween them. It will be apparent to those skilled in the art that theremay be a number of other ion optical elements in the system. Other typeof mass analyzer such as single quadrupole, ion trap (3D or 2D), hybridanalyzer (quadrupole-time of flight, quadrupole-linear ion trap,quadrupole-orbitrap), orbitrap or time-of-flight, could also be used.

In operation, a sample containing or suspected of containing ananalyte(s) of interest can be prepared in accordance with variousmethods as known in the art for introduction into the differentialmobility spectrometer 110. The ions can be generated adjacent the inlet150 of the curtain chamber 130 and then transported through thedifferential mobility spectrometer 110 that is configured to remove bothlow-mass ions (e.g., ionized solvent molecules exhibiting less than 200m/z or less than 100 m/z) and high-mass ions (e.g., charged residuesexhibiting greater than 2000 m/z or a mass greater than 2000 amu). Theremainder of ions (e.g., ions exhibiting m/z in a range of about 200 Dato about 2000 Da) can be transmitted by the differential mobilityspectrometer 110 to downstream mass analyzer elements 150, 150 a forfurther analysis or detection, as is known in the art.

As indicated above, contamination of mass spectrometer ion paths bysubstances created during the electrospray ionization of samples andsolvents is of major concern. Costly and time consuming cleaningprocedures are required to ameliorate the problem. Extensive effortshave been employed to develop devices to minimize or eliminate thisproblem. To date, the field has focused on the use of shadow stops orcurvatures in ion guides located in the vacuum system of the massspectrometer to filter neutral components thought to be the cause ofcontamination from the ion beam. Neutral particles follow a straighttrajectory through curved fields whereas ions and charged particlesfollow the fields. If neutral particles were the primary source ofcontamination, then curved ion guides or shadow stops would eliminatethem and prevent them from going deeper into the vacuum system wherethey can do more damage. If, however, the main source of contaminationwas charged particles and high ion currents from electrospray solvents,this approach would serve no purpose because the charged contaminantswould follow the curved fields and travel around any shadow stops.

Furthermore, the present teachings are based on the discovery that ahigh transmission, low resolution ion mobility device can filter thehigh mass ions or charged debris to keep the vacuum system of a massspectrometer clean for long periods of time. The device configurationtakes into account the residence time of the ions through the ionmobility spectrometer, the gap height between the electrodes of the ionmobility spectrometer, and the maximum separation voltage applied to theion mobility spectrometer, wherein a ratio of the residence time of theions through the ion mobility spectrometer to the product of gap heightbetween electrodes of the ion mobility spectrometer and the maximumseparation voltage being less than 0.002. In various aspects, a ratio ofthe residence time of the ions through the ion mobility spectrometer tothe product of gap height between the electrodes of the ion mobilityspectrometer and the maximum separation voltage applied to theelectrodes of the ion mobility spectrometer being less than 0.0015.Conventional prior art ion mobility devices have been configured toachieve high selectivity to maximize the separation power at the expenseof transmission of the ions and sensitivity differing from theApplicants' counter-intuitive teachings of a low resolution ion mobilitydevice designed to filter charged particles prior to the vacuum systemwhile achieving high transmission of ions.

In various aspects, the residence time of the ions can be less than 100ms. In various aspects, the gap height can be between 0.02 and 5millimeters. In various aspects, the SV comprises an RF signal appliedto the electrodes, and including a CoV comprised of a DC signal appliedto the electrodes, and wherein the RF and DC signals are configured togenerate a fringing field in proximity of said input end of the ionmobility spectrometer effective to cause said ions having a selectedmass to follow off-axis trajectories to collide with said electrodes inproximity to said input end. In various aspects, the method and systemfurther comprise selecting a transit time of the ions through the ionmobility spectrometer to facilitate transit of analytes of interestthrough the ion mobility spectrometer. In various aspects, the transittime can be selected to provide transmission efficiency of greater than50% for a broad mass range of ions. In various aspects, the ion mobilityspectrometer comprises a differential mobility spectrometer or a FAIMSsystem.

Experiments were conducted to determine whether the main source of massspectrometer contamination was from neutral particles or chargedsubstances, the results are shown in FIGS. 9A-9C. The experiments weredone on a commercial electrospray mass spectrometer with an atmosphericinterface depicted in FIG. 5 with the DMS cell both installed andremoved. The interface comes equipped with a counter current flow ofgas, the purpose of which is to blow neutral particles away from theatmospheric entrance aperture while ions and charged particles followthe electric fields and travel against the curtain gas flow. Anaccelerated contamination test was developed using a common commercialbiological buffer solution referred to as Hank's buffer. The aqueousHank's buffer solution was infused under normal operating conditionswith the high voltage applied to the pneumatically nebulizedelectrospray emitter to charge the droplets with the curtain gas on atall times at sufficient velocity to eliminate neutrals. As shown in FIG.9A, after 15 hours the atmospheric aperture was clogged with materialfrom the sample when the ion source was operated in the normal way, withthe sprayer voltage on. For the material to have penetrated the curtaingas, it had to be charged.

The experiment was repeated with all conditions identical except a DMScell according to the Applicants' teachings was installed. As seen inFIG. 9B, after 24 hours the atmospheric aperture was free of any visiblecontamination. All of the charged debris was deflected at the entranceof the cell and most importantly before entering the vacuum system ofthe mass spectrometer where the serious damage can occur. As in thefirst case, the curtain gas was on at sufficient levels to eliminateneutral materials.

To make sure the curtain gas was deflecting neutral materials that couldbe generated by the spraying of Hank's buffer, a third experiment wasdone with the results shown in FIG. 9C. The DMS cell was removed, andthe same sample run this time spraying only by means of the pneumaticnebulizer; the high voltage to the electrospray emitter was off. Underthis condition, no charging of the sample is occurring but abundantneutral droplets and uncharged particles are created. No build up ofdebris was observed on the atmospheric aperture proving that the curtaingas was effectively eliminating all neutral materials, and the source ofthe mass analyzer contamination was from charged particles and ions.

Photographs of critical lens elements from the mass spectrometer inletand inside the vacuum further corroborating the effectiveness of the DMSas a charged debris filter according to the Applicants' teachings areshown in FIGS. 10A-10B. Critical lenses inside the vacuum system wereobserved to be contaminated after the experiment in FIG. 9A as shown inFIG. 10A and free of any debris under conditions in FIG. 9B as shown inFIG. 10B.

Charged materials generated by an electrospray process can take twoforms. It can be in the form of charged molecules (ions); the vastmajority of which is the electrospray solvent. The overwhelmingabundance and intensity of the ion current from the solvent ions can bereadily seen in a mass spectrum. It may be possible that they can be asource of ion burn on critical lenses inside the vacuum system. But,solvent ions are volatile and cannot be expected to build up debris tothe extent as that shown in FIG. 9A where the vacuum system was nearlyplugged off. The charged debris that accumulated can also be coming fromthe dissolved substances in the sample.

Subsequent to this experiment, the inventors have discovered theexistence of previously unknown physical entities in the form ofsubstances with very high mass to charge ratio beyond the mass range ofmass spectrometers. We have characterized their nature with a novel scanmode for a tandem mass spectrometer that we developed specifically forthis purpose. These substances are ubiquitous and an inheritedby-product of electrospray ionization. All indications are that they area major source of mass spectrometer analyzer contamination. It is thesesubstances, in combination with the extremely high ion currents that areproduced by electrospray from the low mass solvent ions, which can causethe fouling of critical components in the ion path located in the vacuumsystem of mass spectrometers leading to distortions in the electricfields of the mass filters and focusing lenses resulting in reducedperformance. An understanding of these substances and their effect onanalyzer contamination is neither known nor obvious in the current stateof the science involving mass spectrometry.

The scan mode we developed to prove the existence of these high masscharged particles is described below and is referred to as the “Asteroidscan.” It has no analytical purpose other than as a means to observe andquantitate these materials. The Asteroid scan can be done on a triplequadrupole mass spectrometer. All samples will produce asteroids, butthe more organic and inorganic solutes in the electrospray solvent, themore asteroids are produced. The asteroids can be tracked by adding tothe solvent a standard reference compound such as reserpine whichbecomes trapped in the asteroid during the ionization process. Thesample is infused into the ion source. Quadrupole 1 mass filter is setto open resolution at m/z 1250 by dropping the mass resolving DC voltageramp. Under these conditions, no ions below m/z 1000 pass Q1, but allions and charged particles above m/z 1000 pass. Collision gas is putinto the collision cell, and the collision energy is initially set to 0volts. When quadrupole 3 is scanned, the resulting mass spectrum showsno ions at any mass. As the collision energy is raised to 150 eV, ionsfrom the seed compound begin to appear in the Q3 spectrum and increasein intensity as they are released from the high mass charged particle.

FIGS. 1(A)-1(C) provide an example. FIG. 1(A) is a standard product ionscan of reserpine to use as a reference for identifying the molecularion and fragment ions from reserpine during subsequent asteroid scans.Reserpine typically fragments at 47 eV collision energy. When thecollision energy is set to 0 during the asteroid scan, no ions,including the molecular ion at m/z 609, can be observed. As seen in FIG.1(B), at 50 eV, the molecular ion from reserpine at m/z 609 is releasedfrom the asteroid and appears in the Q3 spectrum. It is not fragmentingas it did in the conventional product ion scan at 47 eV because much ofthe vibrational energy is absorbed by the other components of the highmass charged particle. In FIG. 1(C), at 100 eV, the product ionfragments of reserpine are observed along with many other unidentifiedions. The unidentified ions are coming from other unknown components ofthe asteroid or charged particle.

FIG. 11 shows that the amount of material captured in the asteroids canbe significant and that they are filtered by the DMS fields according tothe Applicants' teachings. In this case, Q3 is set to monitor only theions from reserpine and no others. At 5 eV collision energy, virtuallyno signal is observed, and at 70 eV several orders of magnitude signalrise is seen. The DMS cell is installed but both SV and CoV are off sono filtering is occurring. When the CoV is turned on to 100V, theasteroids are removed and return when the voltage is turned back off.When the SV is set to 4000V, a similar filtering action is observed.This data validates the photographic observations in FIGS. 9A-9C and10A-10B.

The understanding of the existence of these high mass charged particlesand their role in analyzer contamination is new knowledge. It presentsthe opportunity for a new application of a DMS based device that wouldrequire design characteristics substantially different from the currentstatus that teaches away from optimizing the performance specificationsof current generation DMS mobility cells. The ideal contamination filterwould first remove charged particles before entering the vacuum systemwhich is essentially what current DMS cells do. But, it would also havebroad band pass characteristics which would limit its separationcapability to only the removal of high mass charged particles and lowmass solvent ions. This would mean the design would drive toward verylow resolution and peak capacity instead of high resolution and peakcapacity. The separation of isobars would no longer be of any relevanceto the design of this device given its primary application of themaximization of ion transmission whereas in the prior art, this figureof merit was secondary to resolution and peak capacity.

In order to achieve the goal of maximum ion transmission efficiencywhile maintaining adequate resolution and peak capacity to serve as abroad band pass contamination filter, the relationship of three keydesign elements are considered. These elements are ion flight time, cellgap height, and maximum separation voltage. Following is data describingthe effect that each one has on the three performance characteristicsfor the basic DMS described in FIG. 5. The relative trends that thesefigures of merit exhibit will be generalizable to any particular designand thus are not limited to any particular design. In addition thedesign specifications for the currently described commercial andnoncommercial DMS and FAIMS analyzers will be described and compared tothe optimized values we propose for an ideal contamination filter.

Gap height is considered in FIG. 12. Ion transmission trends in theopposite direction of resolution and peak capacity for a fixed residencetime. From the graph, it would appear that an ideal contamination filterwould have the largest gap height possible to maximize transmission, allother elements being equivalent as was done to generate the performancedata for this particular cell described with reference to FIGS. 3 and 5.However, as elaborated earlier, optimization of each performancecharacteristic requires a balancing of several important designelements. Superimposed on the graph in circles are the gap heights ofthe various commercial and non-commercial DMS and FAIMS devices thathave been described in the general literature, as well as two versionsof cells optimized as contamination filters. The performance trends onthe y-axis generally apply to all but their position on the x-axisvaries for each individual system as the gap height is changed. Gapheights can span a large range with very little distinguishing thecurrent generation high resolution devices from the proposedcontamination filters. A=Contamination filter 1. B=Contamination filter2. C=Commercial DMS-MS system. D. Commercial micro machined DMS-MSsystem. E. Commercial cylindrical FAIMS-MS system. F. Non-commercialDMS-MS system. G. Non-commercial DMS-MS system. H. Commercialcylindrical FAIMS-MS system.

Separation voltage (SV) is considered in FIG. 13. Ion transmission,resolution and peak capacity track together. From the graph, it wouldappear that an ideal contamination filter could not be designed as hightransmission would bring with it high resolution and peak capacity whichis not desirable for a broad band pass device. The balancing of theother two design elements can counter this effect. Superimposed on thegraph in circles are the separation voltages of the various commercialand non-commercial DMS and FAIMS devices as well as two versions ofcells optimized as contamination filters. The performance trends on they-axis generally apply to all but their position on the x-axis variesfor each individual system as the SV is changed. Separation voltagevalues can span a large range with very little distinguishing thecurrent generation high resolution devises from the proposedcontamination filters. A=Contamination filter 1. B=Contamination filter2. C=Commercial DMS-MS system. D. Commercial micromachined DMS-MSsystem. E. Commercial cylindrical FAIMS-MS system. F. Non-commercialDMS-MS system. G. Non-commercial DMS-MS system. H. Commercialcylindrical FAIMS-MS system.

Flight time also known as residence time is considered in FIG. 14. Iontransmission trends strongly in the opposite direction of resolution andpeak capacity. In addition, as the residence time of the ions increases,ion losses become more prevalent, as shown with the diamonds labeledIntensity. From the graph, it would appear that an ideal contaminationfilter would have the shortest possible flight time to maximizetransmission and reduce resolution and peak capacity, all other elementsbeing equivalent as was done to generate the performance data for thisparticular cell described with reference to FIGS. 3 and 5. Once again,the balancing of the other design elements provides flexibility, and thescatter between the various commercial and non-commercial DMS devicesshows no distinguishing cut-off across the boards from versions of cellsoptimized as contamination filters. The performance trends on the y-axisgenerally apply to all but their position on the x-axis varies for eachindividual system as the flight time is changed. However, those shownwith the very long flight times have the opportunity to provide thegreatest resolution provided the other design parameters are welloptimized. A=Contamination filter 1. B=Contamination filter 2.C=Commercial DMS-MS system. D. Commercial micromachined DMS-MS system.E. Commercial cylindrical FAIMS-MS system. F. Non-commercial DMS-MSsystem. G. Non-commercial DMS-MS system. H. Commercial cylindricalFAIMS-MS system.

The three most important design elements determining the performancecharacteristics of resolution, peak capacity and transmission are flighttime, gap height, and separation voltage. They operate together in apartial inverse relationship we refer to as the Resolution-TransmissionIndex or RT Index mathematically expressed as:

RT=τ/hSv   (Equation 5)

where τ is the flight time, h is the gap height, and Sv is theseparation voltage.

RT Index is considered in FIG. 15. When these design elements areconsidered together in this relationship, and not individually as in theprevious three graphs, the plot of the three performance traits can bemade on a universal scale applicable to all variations of DMS systemsbecause their interdependence is accounted for in the equation. For allcombinations of these design elements, the relative performance graphsapply allowing each to be compared to the other with respect to theirperformance potentials. At one extreme, the E-H group combines the threedesign elements to achieve the highest possible resolution their devicescan deliver at a severe loss of transmission showing RT indexes that arevery large. Notice the non-linearity of the x-axis with the break at anRT value of 0.01. At the other extreme, the contamination filtersdeliver the maximum ion transmission efficiency their devices candeliver at a cost of resolution and peak capacity which is designed tobe sufficient to filter charged debris and low mass solvent ions. In themiddle, are analytical devices that try to reach a reasonable compromiseto serve as general selectivity enhancement elements for massspectrometry coupling. The contamination filters reside in a region ofthe RT index distinct and unique and never exploited before largely dueto a lack of appreciation of the potential for this application and alack of knowledge in the scientific community regarding the particularsubstances that required filtering, specifically charged high massparticles in addition to low mass solvent ions. This region of designparameters is bounded by a maximum value of RT=0.002 defining athreshold that has hereto for not been breached because of a lack ofunderstanding of its utility and the non-obviousness of its application.

The value of a low resolution device is that it allows a large range ofanalyte ions with a broad range of mobilities to pass without having toalter the SV or CoV voltages. This helps keep the duty cycle of thesystem to a maximum. FIGS. 16A and 16B demonstrate this principle andalso highlight the extent to which unwanted low mass ion current can beeliminated. Although it is not likely that this low mass solventdominated ion current contributes to the occlusion of the vacuumentrance seen on the right of FIG. 16A and in FIG. 9A because it isinherently volatile, it's great intensity can lead to ion burns oncritical focusing elements inside the vacuum system as shown in FIG.10A. The massive charged particles are responsible for the occlusion andare eliminated as shown in the photographs in FIGS. 9B and 10B. Althoughuniquely designed to pass broad bands of mobility space, thecontamination filter does provide control over the position of thiswindow by adjusting the SV and CoV if fine tuning the filter is requiredfor specific applications. Because it is a mobility filter, it does notbound precise m/z ranges and apriory knowledge of the mobility of thetargeted analytes is not generally required because the resolution is solow. The broad band pass nature of the contamination filter compared toa high resolution DMS device can also be appreciated from the ionogramsin FIG. 17, where the term ion scrubber is used to describe the hightransmission mobility filter according to the Applicants' teachings.

The spectra and images in FIGS. 16A-16B show that the degree to whichthe filter is eliminating contamination represents several orders ofmagnitude improvement over not using the device. In principle, thiscould extend the lifetime of mass spectrometers between costly and timeconsuming cleaning and repair from a few months to several years.

In accordance with the Applicants' teachings, the majority ofcontaminating species are being kept out of the vacuum system and awayfrom the ion entrance aperture of the mass spectrometer due to theApplicants' high transmission mobility filter ion scrubber. FIGS.18A-18D show where the contamination is going. Some material isdeposited on the outside of the atmospheric curtain plate as wouldnormally be expected and happens whether or not the filter is installedas shown in FIG. 18A. It produces no detrimental effect on the massspectrometer when deposited in this region. But a large amount of debrismaterial can be observed on the entrance to the planar DMS cell whichvisually appears end on as a slot in FIG. 18B. If the cell isdisassembled, and the inside of the separation channel is visuallyinspected, debris is observed to accumulate to the greatest degree inthe first few mm of the ion path as shown in FIGS. 18C and 18D. Thisregion correlates with the presence of strong fringing fields generatedby the RF and DC potentials as shown in the simulations of both ions andcharged particle trajectories in the entrance region of the cell in FIG.19. The simulation shows a charged particle being deflected and strikingthe electrode at the entrance to the cell (1) due to the fringingfields, and an ion (2) passing through the entrance fields. It is likelythat the fringing fields account for the removal of a large portion ofthis material. The cell is in the atmospheric ion source region and canbe easily removed and replaced without breaking vacuum or even requiringthe use of tools. Down time is only a few minutes and can be addressedby unskilled operators. Additionally, the ion beam in this region is notsignificantly affected by the accumulation of debris. This is becausethe trajectory of ions in this region is primarily controlled by stronggas flows so perturbations in the fields at the entrance do notsignificantly reduce analyte ion transmission or resolution.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting. While the Applicants' teachingsare described in conjunction with various embodiments, it is notintended that the applicants' teachings be limited to such embodiments.On the contrary, the Applicants' teachings encompass variousalternatives, modifications, and equivalents, as will be appreciated bythose of skill in the art.

1-8. (canceled)
 9. A system for analyzing ions comprising: an ionsource; a low resolution, high transmission ion mobility spectrometerfor reducing contamination having an input end for receiving ions fromthe ion source and an output end, the ion mobility spectrometer havingan internal operating pressure, electrodes, and at least one voltagesource for providing DC and RF voltages to the electrodes; a massspectrometer in fluid communication with the ion mobility spectrometerfor receiving the ions from the output end of ion mobility spectrometer;and a controller operably coupled to the ion mobility spectrometer andconfigured to control the DC and RF voltages; and wherein the ionmobility spectrometer is configured such that a ratio of a residencetime of the ions through the ion mobility spectrometer to a product ofgap height between electrodes of the ion mobility spectrometer and amaximum separation voltage applied to the electrodes of the ion mobilityspectrometer being less than 0.002 second/(meter*volt).
 10. The systemof claim 9, wherein the spectrometer is configured such that the ratioof the residence time of the ions through the ion mobility spectrometerto the product of gap height between electrodes of the ion mobilityspectrometer and the maximum separation voltage applied to theelectrodes of the ion mobility spectrometer being less than 0.0015second/(meter*volt).
 11. The system of claim 9, wherein the residencetime of the ions is less than 100 milliseconds.
 12. The system of claim9, wherein the gap height is between 0.02 and 5 millimeters.
 13. Thesystem of claim 9, wherein the separation voltage (SV) comprises an RFsignal applied to the electrodes, and including a compensation voltage(CoV) comprised of a DC signal applied to the electrodes and wherein theRF and DC signals are configured to generate a fringing field inproximity of said input end of the ion mobility spectrometer effectiveto cause said ions having a selected mass to follow off-axistrajectories to collide with said electrodes in proximity to said inputend.
 14. The system of claim 9, further comprising selecting a transittime of the ions through the ion mobility spectrometer to facilitatetransit of analytes of interest through the ion mobility spectrometer.15. The system of claim 14, wherein the transit time is selected toprovide transmission efficiency of greater than 50% for a broad massrange of ions.
 16. The system of claim 9, wherein the ion mobilityspectrometer comprises a differential mobility spectrometer or FAIMSspectrometer.
 17. A method of operating a mass spectrometer systemincluding an ion mobility spectrometer and a mass spectrometer in fluidcommunication with the ion mobility spectrometer, the method comprising:ionizing a sample to generate a plurality of ions; introducing saidplurality of ions into an input end of the ion mobility spectrometer;transporting said plurality of ions in a drift gas through the ionmobility spectrometer from the input end to an output end thereof;filtering ions having a mass greater than about 2000 amu from the driftgas as the plurality of ions are transported through the ion mobilityspectrometer; and filtering ions having a mass less than about 200 amufrom the drift gas as the plurality of ions are transported through theion mobility spectrometer.
 18. A system for analyzing ions comprising:an ion source; an ion mobility spectrometer having an input end forreceiving ions from the ion source and an output end, the ion mobilityspectrometer having an internal operating pressure, electrodes, and atleast one voltage source for providing DC and RF voltages to theelectrodes; a mass spectrometer in fluid communication with the ionmobility spectrometer for receiving the ions from the output end of theion mobility spectrometer; and a controller operably coupled to the ionmobility spectrometer and configured to control the DC and RF voltagessuch that the ion mobility spectrometer preferentially transport ionshaving a mass in a range from about 200 amu to about 2000 amu to theoutput end of the ion mobility spectrometer.